An IDR-dependent mechanism for nuclear receptor control of Mediator interaction with RNA polymerase II.

The essential Mediator (MED) coactivator complex plays a well-understood role in regulation of basal transcription in all eukaryotes, but the mechanism underlying its role in activator-dependent transcription remains unknown. We investigated modulation of metazoan MED interaction with RNA polymerase II (RNA Pol II) by antagonistic effects of the MED26 subunit and the CDK8 kinase module (CKM). Biochemical analysis of CKM-MED showed that the CKM blocks binding of the RNA Pol II carboxy-terminal domain (CTD), preventing RNA Pol II interaction. This restriction is eliminated by nuclear receptor (NR) binding to CKM-MED, which enables CTD binding in a MED26-dependent manner. Cryoelectron microscopy (cryo-EM) and crosslinking-mass spectrometry (XL-MS) revealed that the structural basis for modulation of CTD interaction with MED relates to a large intrinsically disordered region (IDR) in CKM subunit MED13 that blocks MED26 and CTD interaction with MED but is repositioned upon NR binding. Hence, NRs can control transcription initiation by priming CKM-MED for MED26-dependent RNA Pol II interaction.

Establishing and clinically validating a machine learning model for predicting unplanned reoperation risk in colorectal cancer.

BACKGROUND: Colorectal cancer significantly impacts global health, with unplanned reoperations post-surgery being key determinants of patient outcomes. Existing predictive models for these reoperations lack precision in integrating complex clinical data. AIM: To develop and validate a machine learning model for predicting unplanned reoperation risk in colorectal cancer patients. METHODS: Data of patients treated for colorectal cancer (n = 2044) at the First Affiliated Hospital of Wenzhou Medical University and Wenzhou Central Hospital from March 2020 to March 2022 were retrospectively collected. Patients were divided into an experimental group (n = 60) and a control group (n = 1984) according to unplanned reoperation occurrence. Patients were also divided into a training group and a validation group (7:3 ratio). We used three different machine learning methods to screen characteristic variables. A nomogram was created based on multifactor logistic regression, and the model performance was assessed using receiver operating characteristic curve, calibration curve, Hosmer-Lemeshow test, and decision curve analysis. The risk scores of the two groups were calculated and compared to validate the model. RESULTS: More patients in the experimental group were ≥ 60 years old, male, and had a history of hypertension, laparotomy, and hypoproteinemia, compared to the control group. Multiple logistic regression analysis confirmed the following as independent risk factors for unplanned reoperation (P < 0.05): Prognostic Nutritional Index value, history of laparotomy, hypertension, or stroke, hypoproteinemia, age, tumor-node-metastasis staging, surgical time, gender, and American Society of Anesthesiologists classification. Receiver operating characteristic curve analysis showed that the model had good discrimination and clinical utility. CONCLUSION: This study used a machine learning approach to build a model that accurately predicts the risk of postoperative unplanned reoperation in patients with colorectal cancer, which can improve treatment decisions and prognosis.

Metagenomic investigation of antibiotic resistance genes and resistant bacteria contamination in pharmaceutical plant sites in China.

Pharmaceutical plant sites play a significant role in the dissemination of antibiotic resistance genes (ARGs) into the environment. It is imperative to comprehensively monitor of ARGs across various environmental media at these sites. This study focused on three pharmaceutical plants, two located in North China and one in South China. Through metagenomic approaches, we examined the composition, mobility potential, and bacterial hosts of ARGs in diverse media such as process water, groundwater, topsoil, soil cores, and pharmaceutical fermentation residues across diverse environmental matrices, including topsoil, soil cores, process water, groundwater, and pharmaceutical fermentation residues. We identified a wide array of ARGs, comprising 21 types and 740 subtypes, with process water exhibiting the highest abundance and diversity. Treatment processes varied in their efficacy in eliminating ARGs, and the clinically relevant ARGs should also be considered when evaluating wastewater treatment plant efficiency. Geographical distinctions in groundwater ARG distribution between northern and southern regions were observed. Soil samples from the three sites showed minimal impact from pharmaceutical activity, with vancomycin-resistance genes being the most prevalent. High levels of ARGs in pharmaceutical fermentation residues underscore the necessity for improved waste management practices. Metagenomic assembly revealed that plasmid-mediated ARGs were more abundant than chromosome-mediated ARGs. Metagenome-assembled genomes (MAGs) analysis identified 166 MAGs, with 62 harboring multiple ARGs. Certain bacteria tended to carry specific types of ARGs, revealing distinct host-resistance associations. This study enhances our understanding of ARG dissemination across different environmental media within pharmaceutical plants and underscores the importance of implementing strict regulations for effluent and residue discharge to control ARG spread.

Comparison of clinicopathological features between cerebral cystic and alveolar echinococcosis: analysis of 27 cerebral echinococcosis cases in Xinjiang, China.

BACKGROUND: Cerebral echinococcosis is relatively rare, and it is important to distinguish cerebral cystic echinococcosis (CCE) from cerebral alveolar echinococcosis (CAE) in terms of pathological diagnosis. We aim to describe the different clinicopathological features among patients with CCE and CAE. METHODS: We collected 27 cases of cerebral echinococcosis which were diagnosed in the Department of Pathology of the First Affiliated Hospital of Xinjiang Medical University from January 1, 2012, to June 30, 2023. We compared the patients' clinical characteristics, MRI features, and pathologic manifestations of CCE and CAE. RESULTS: Among 27 cases of cerebral echinococcosis, 23 cases were CAE and 4 cases were CCE. The clinical manifestations of both CCE and CAE patients mainly included headache (21 patients, 77.78%), limb movement disorders (6 patients, 22.22%), epileptic seizures (4 patients, 14.81%) and visual disturbances (2 patients, 7.41%). The average onset age of CAE cases was 34.96 ± 11.11 years, which was 9.00 ± 7.26 years in CCE cases. All CAE patients presented with multiple involvements in the brain and extracranial organs while all CCE patients observed a solitary lesion in the brain and 3 CCE cases had no extracranial involvement. Lesions of CCE in MRI showed a single isolated circular, which was well demarcated from the surrounding tissues and with no obvious edema around the lesions, whereas CAE lesions presented as multiple intracranial lesions, with blurred edges and edema around the lesions, and multiple small vesicles could be observed in the lesions. The edge of CAE lesions could be enhanced, while CCE lesions have no obvious enhancement. CCE foci were clear cysts with a wall of about 0.1 cm. Microscopically, the walls of the cysts were characterized by an eosinophilic keratin layer, which was flanked on one side by basophilic germinal lamina cells, which were sometimes visible as protocephalic nodes. While the CAE lesion was a nodular structure with a rough and uneven nodule surface, and the cut section was cystic and solid; microscopically, the CAE lesion had areas of coagulative necrosis, and the proto-cephalic nodes were barely visible. Inflammatory cell areas consisting of macrophages, lymphocytes, epithelioid cells, plasma cells, eosinophils, and fibroblasts can be seen around the lesion. Brain tissues in the vicinity of the inflammatory cell areas may show apoptosis, degeneration, necrosis, and cellular edema, while brain tissues a little farther away from the lesion show a normal morphology. CONCLUSIONS: With the low incidence of brain echinococcosis, the diagnosis of echinococcosis and the differential diagnosis of CAE and CCE are challenging for pathologists. Grasping the different clinical pathology characteristics of CAE and CCE is helpful for pathologists to make accurate diagnoses.

Improved YOLO-FastestV2 wheat spike detection model based on a multi-stage attention mechanism with a LightFPN detection head.

The number of wheat spikes has an important influence on wheat yield, and the rapid and accurate detection of wheat spike numbers is of great significance for wheat yield estimation and food security. Computer vision and machine learning have been widely studied as potential alternatives to human detection. However, models with high accuracy are computationally intensive and time consuming, and lightweight models tend to have lower precision. To address these concerns, YOLO-FastestV2 was selected as the base model for the comprehensive study and analysis of wheat sheaf detection. In this study, we constructed a wheat target detection dataset comprising 11,451 images and 496,974 bounding boxes. The dataset for this study was constructed based on the Global Wheat Detection Dataset and the Wheat Sheaf Detection Dataset, which was published by PP Flying Paddle. We selected three attention mechanisms, Large Separable Kernel Attention (LSKA), Efficient Channel Attention (ECA), and Efficient Multi-Scale Attention (EMA), to enhance the feature extraction capability of the backbone network and improve the accuracy of the underlying model. First, the attention mechanism was added after the base and output phases of the backbone network. Second, the attention mechanism that further improved the model accuracy after the base and output phases was selected to construct the model with a two-phase added attention mechanism. On the other hand, we constructed SimLightFPN to improve the model accuracy by introducing SimConv to improve the LightFPN module. The results of the study showed that the YOLO-FastestV2-SimLightFPN-ECA-EMA hybrid model, which incorporates the ECA attention mechanism in the base stage and introduces the EMA attention mechanism and the combination of SimLightFPN modules in the output stage, has the best overall performance. The accuracy of the model was P=83.91%, R=78.35%, AP= 81.52%, and F1 = 81.03%, and it ranked first in the GPI (0.84) in the overall evaluation. The research examines the deployment of wheat ear detection and counting models on devices with constrained resources, delivering novel solutions for the evolution of agricultural automation and precision agriculture.

Recent advances in the development of tumor microenvironment-activatable nanomotors for deep tumor penetration.

Cancer represents a significant threat to human health, with the use of traditional chemotherapy drugs being limited by their harsh side effects. Tumor-targeted nanocarriers have emerged as a promising solution to this problem, as they can deliver drugs directly to the tumor site, improving drug effectiveness and reducing adverse effects. However, the efficacy of most nanomedicines is hindered by poor penetration into solid tumors. Nanomotors, capable of converting various forms of energy into mechanical energy for self-propelled movement, offer a potential solution for enhancing drug delivery to deep tumor regions. External force-driven nanomotors, such as those powered by magnetic fields or ultrasound, provide precise control but often necessitate bulky and costly external equipment. Bio-driven nanomotors, propelled by sperm, macrophages, or bacteria, utilize biological molecules for self-propulsion and are well-suited to the physiological environment. However, they are constrained by limited lifespan, inadequate speed, and potential immune responses. To address these issues, nanomotors have been engineered to propel themselves forward by catalyzing intrinsic "fuel" in the tumor microenvironment. This mechanism facilitates their penetration through biological barriers, allowing them to reach deep tumor regions for targeted drug delivery. In this regard, this article provides a review of tumor microenvironment-activatable nanomotors (fueled by hydrogen peroxide, urea, arginine), and discusses their prospects and challenges in clinical translation, aiming to offer new insights for safe, efficient, and precise treatment in cancer therapy.

Unraveling schizophrenia's genetic complexity through advanced causal inference and chromatin 3D conformation.

Schizophrenia is a polygenic complex disease with a heritability as high as 80 %, yet the mechanism of polygenic interaction in its pathogenesis remains unclear. Studying the interaction and regulation of schizophrenia susceptibility genes is crucial for unraveling the pathogenesis of schizophrenia and developing antipsychotic drugs. Therefore, we developed a bioinformatics method named GRACI (Gene Regulation Analysis based on Causal Inference) based on the principles of information theory, a causal inference model, and high order chromatin 3D conformation. GRACI captures the interaction and regulatory relationships between schizophrenia susceptibility genes by analyzing genotyping data. Two datasets, comprising 1459 and 2065 samples respectively, were analyzed, and the gene networks from both datasets were constructed. GRACI showcased superior accuracy when compared to widely adopted methods for detecting gene-gene interactions and intergenic regulation. This alignment was further substantiated by its correlation with chromatin high-order conformation patterns. Using GRACI, we identified three potential genes-KCNN3, KCNH1, and KCND3-that are directly associated with schizophrenia pathogenesis. Furthermore, the results of GRACI on the standalone dataset illustrated the method's applicability to other complex diseases. GRACI download: https://github.com/liuliangjie19/GRACI.

NS2 induces an influenza A RNA polymerase hexamer and acts as a transcription to replication switch.

Genome transcription and replication of influenza A virus (FluA), catalyzed by viral RNA polymerase (FluAPol), are delicately controlled across the virus life cycle. A switch from transcription to replication occurring at later stage of an infection is critical for progeny virion production and viral non-structural protein NS2 has been implicated in regulating the switch. However, the underlying regulatory mechanisms and the structure of NS2 remained elusive for years. Here, we determine the cryo-EM structure of the FluAPol-NS2 complex at ~3.0 Å resolution. Surprisingly, three domain-swapped NS2 dimers arrange three symmetrical FluPol dimers into a highly ordered barrel-like hexamer. Further structural and functional analyses demonstrate that NS2 binding not only hampers the interaction between FluAPol and the Pol II CTD because of steric conflicts, but also impairs FluAPol transcriptase activity by stalling it in the replicase conformation. Moreover, this is the first visualization of the full-length NS2 structure. Our findings uncover key molecular mechanisms of the FluA transcription-replication switch and have implications for the development of antivirals.

Evaluating genomic inbreeding of two Chinese yak (Bos grunniens) populations.

BACKGROUND: Yaks are a vital livestock in the Qinghai-Tibetan Plateau area for providing food products, maintaining sustainable ecosystems, and promoting cultural heritage. Because of uncontrolled mating, it is impossible to estimate inbreeding level of yak populations using the pedigree-based approaches. With the aims to accurately evaluate inbreeding level of two Chinese yak populations (Maiwa and Jiulong), we obtained genome-wide single nucleotide polymorphisms (SNPs) by DNA sequencing and calculated five SNP-by-SNP estimators ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text]), as well as two segment-based estimators of runs of homozygosity (ROH, [Formula: see text]) and homozygous-by-descent (HBD, [Formula: see text]). Functional implications were analyzed for the positional candidate genes located within the related genomic regions. RESULTS: A total of 151,675 and 190,955 high-quality SNPs were obtained from 71 Maiwa and 30 Jiulong yaks, respectively. Jiulong had greater genetic diversity than Maiwa in terms of allele frequency and nucleotide diversity. The two populations could be genetically distinguished by principal component analysis, with the mean differentiation index (Fst) of 0.0054. The greater genomic inbreeding levels of Maiwa yaks were consistently supported by all five SNP-by-SNP estimators. Based on simple proportion of homozygous SNPs ([Formula: see text]), a lower inbreeding level was indicated by three successfully sequenced old leather samples that may represent historical Maiwa yaks about five generations ago. There were 3304 ROH detected among all samples, with mean and median length of 1.97 Mb and 1.0 Mb, respectively. A total of 94 HBD segments were found among all samples, whereas 92 of them belonged to the shortest class with the mean length of 10.9 Kb. Based on the estimates of [Formula: see text] and [Formula: see text], however, there was no difference in inbreeding level between Maiwa and Jiulong yaks. Within the genomic regions with the significant Fst or enriched by ROH, we found several candidate genes and pathways that have been reported to be related to diverse production traits in farm animals. CONCLUSIONS: We successfully evaluated the genomic inbreeding level of two Chinese yak populations. Although different estimators resulted in inconsistent conclusions on their genomic inbreeding levels, our results may be helpful to implement the genetic conservation and utilization programs for the two yak populations.

[Quality control mode between Lonicera macranthoides and L. japonica based on multi-elemental difference through inductively coupled plasma mass spectrometry].

Numerous studies show that Lonicera macranthoides and L. japonica have significant differences in organic matter. However, there is still a lack of research on inorganic elements between them. In this study, a non-targeted elemental metabolomics method was established by inductively coupled plasma mass spectrometry(ICP-MS), so as to compare the overall differences of inorganic elements between L. macranthoides and L. japonica. In addition, the differential markers were screened, and these differential markers were quantitatively analyzed by the targeted method. The non-targeted elemental metabolomics showed that the established mathematical model could reflect the difference in element content between L. macranthoides and L. japonica. Four inorganic elements such as ~(55)Mn, ~(209)Bi, ~(111)Cd, and ~(85)Rb were confirmed as the differential markers of L. macranthoides and L. japonica based on the screening principles of variable importance in the projection(VIP) value>2.0, P<0.01 and fold change(FC) value>1.2 or <0.80. The targeted quantitative results showed that the content of ~(209)Bi in L. japonica was significantly higher than that in L. macranthoides, while ~(55)Mn, ~(111)Cd, and ~(85)Rb in L. macranthoides were significantly higher than that in L. japonica. The non-targeted and targeted elemental metabolomics methods based on ICP-MS can significantly reflect the overall differences in inorganic elements between L. macranthoides and L. japonica. Exploring the differences between them from the perspective of elements can partly reflect the differences in their drug properties and lay a foundation for further study on the quality control mode of inorganic elements in L. macranthoides and L. japonica and their pharmacological effects.

Consensus for antifungal stewardship in China (2024 edition).

Background: Invasive fungal disease (IFD) has become a serious threat to human health in China and around the world, with high mortality and morbidity. Currently, the misdiagnosis rate of IFD is extremely high, compounded with the low quality of prescription antifungals and the high incidence of adverse events associated with IFD treatment, resulting in lengthy hospitalization, low clinical response, and high disease burden, which have become serious challenges in clinical practice. Antifungal stewardship (AFS) can not only significantly increase the early diagnosis rate of IFD, reduce inappropriate utilization of antifungal drugs, improve patient prognosis, but can also improve therapeutic safety and reduce healthcare expenses. Thus, it is urgent to identify key AFS metrics suitable for China's current situation. Methods: Based on metrics recommended by international AFS consensuses, combined with the current situation of China and the clinical experience of authoritative experts in various fields, several metrics were selected, and experts in the fields of respiratory diseases, hematology, intensive care units (ICUs), dermatology, infectious diseases, microbiology laboratory and pharmacy were invited to assess AFS metrics by the Delphi method. Consensus was considered to be reached with an agreement level of ≥80% for the metric. Results: Consensus was reached for 24 metrics, including right patient metrics (n=4), right time metrics (n=3), and right use metrics (n=17). Right use metrics were further subdivided into drug choice (n=8), drug dosage (n=4), drug de-escalation (n=1), drug duration (n=2), and drug consumption (n=2) metrics. Forty-six authoritative experts assessed and reviewed the above metrics, and a consensus was reached with a final agreement level of ≥80% for 22 metrics. Conclusions: This consensus is the first to propose a set of AFS metrics suitable for China, which helps to establish AFS standards in China and is also the first AFS consensus in Asia, and may improve the standard of clinical diagnosis and treatment of IFD, and guide hospitals to implement AFS, ultimately promoting the rational use of antifungal drugs and improving patient prognosis.

Different antithrombotic strategies after coronary artery bypass grafting to prevent adverse events: a retrospective analysis.

OBJECTIVE: Coronary artery bypass grafting (CABG) is associated with antithrombotic therapy in terms of postoperative adverse events; however, it is still unknown whether the early use of such drugs after CABG is safe and effective. In this study, we aim to evaluate the relationship between different postoperative antithrombotic strategies and in-hospital adverse events in patients undergoing isolated coronary artery bypass grafting surgery. METHODS: This was a single-center, retrospective cohort analysis of patients undergoing isolated CABG due to coronary artery disease (CAD) between 2001 and 2012. Data were extracted from the Medical Information Mart for Intensive Care III database. The patients involved were divided into the ASA (aspirin 81 mg per day only) or DAPT (aspirin plus clopidogrel 75 mg per day) group according to the antiplatelet strategy. Patients were also stratified into subgroups based on the type of anticoagulation. The in-hospital risk of bleeding and adverse events was investigated and compared between groups. Propensity score matching (PSM) was performed to reduce the potential effects of a selection bias. RESULTS: A total of 3274 patients were included in this study, with 2358 in the ASA group and 889 in the DAPT group. Following the PSM, no significant difference was seen in the risk of major bleeding between the two groups according to the PLATO, TIMI or GUSTO criteria. There was no difference in the postoperative mortality. In subgroup analysis, patients given anticoagulant therapy had an increased incidence of bleeding-related events. Multivariable analysis revealed that postoperative anticoagulant therapy and the early use of heparin, but not DAPT, were independent predictors of bleeding-related events. CONCLUSIONS: Postoperative DAPT was not associated with an increased occurrence of bleeding-related events in patients undergoing isolated CABG and appears to be a safe antiplatelet therapy. The addition of anticoagulants to antiplatelet therapy increased the risk of bleeding and should be considered cautiously in clinical practice.

Electrically tunable non-radiative lifetime in WS2/WSe2 heterostructures.

Van der Waals heterostructures based on transition metal dichalcogenides (TMDs) have emerged as excellent candidates for next-generation optoelectronics and valleytronics, due to their fascinating physical properties. The understanding and active control of the relaxation dynamics of heterostructures play a crucial role in device design and optimization. Here, we investigate the back-gate modulation of exciton dynamics in a WS2/WSe2 heterostructure by combining time-resolved photoluminescence (TRPL) and transient absorption spectroscopy (TAS) at cryogenic temperatures. We find that the non-radiative relaxation lifetimes of photocarriers in heterostructures can be electrically controlled for samples with different twist-angles, whereas such lifetime tuning is not present in standalone monolayers. We attribute such an observation to doping-controlled competition between interlayer and intralayer recombination pathways in high-quality WS2/WSe2 samples. The simultaneous measurement of TRPL and TAS lifetimes within the same sample provides additional insight into the influence of coexisting excitons and background carriers on the photo-response, and points to the potential of tailoring light-matter interactions in TMD heterostructures.

Antibody Levels and Infection Status of Pertussis in the Population under Pertussis Resurgence in Guangxi in 2018: A Cross-Sectional Survey.

Objective: Pertussis cases have increased markedly since 2018 in Guangxi. The aim of this study was to evaluate antibody levels and the infection status of pertussis in the resident population. Method: A total of 10,215 serum samples from residents were collected from August-November 2018 and tested for anti-pertussis IgG and toxin IgG using the enzyme-linked immunosorbent assay (ELISA). Results: Of the collected samples, 1,833 (17.94%) tested positive for anti-pertussis IgG, with the median concentration of 16.06 IU/mL. Antibody level < 10 IU/mL accounted for more than 60% in children under 4 years of age, but declined with age, whereas the percentages of the other three levels (10-40, 40-50, and ≥ 50 IU/mL) increased almost with age ( P < 0.001). Moreover, 7,924 samples were selected for anti-pertussis toxin IgG, of which 653 (8.24%) tested positive (≥ 40 IU/mL) with the median concentration of 5.89 IU/mL, and 204 participants (2.56%) had recent pertussis infection (≥ 100 IU/mL). Among the different age groups, the highest rates of positivity and recent infection were observed at 11-20 years of age, the lowest positivity rate at 5 years of age, and the lowest recent infection rate at 4 years of age ( P < 0.001, P = 0.005, respectively). Conclusion: The survey results showed that all age groups in Guangxi lacked immunity against pertussis, which was one of the main factors contributing to the resurgence of pertussis in 2018. In addition, the prevalence of pertussis is relatively high in Guangxi, and its incidence is seriously underestimated, especially in adolescents and adults.

Impact of diabetic kidney disease on post-operative complications after primary elective total hip arthroplasty: a nationwide database analysis.

BACKGROUND: The high prevalence of diabetic kidney disease (DKD) in the United States necessitates further investigation into its impact on complications associated with total hip arthroplasty (THA). This study utilizes a large nationwide database to explore risk factors in DKD cases undergoing THA. METHODS: This research utilized a case-control design, leveraging data from the national inpatient sample for the years 2016 to 2019. Employing propensity score matching (PSM), patients diagnosed with DKD were paired on a 1:1 basis with individuals free of DKD, ensuring equivalent age, sex, race, Elixhauser Comorbidity Index (ECI), and insurance coverage. Subsequently, comparisons were drawn between these PSM-matched cohorts, examining their characteristics and the incidence of post-THA complications. Multivariate logistic regression analysis was then employed to evaluate the risk of early complications after surgery. RESULTS: DKD's prevalence in the THA cohort was 2.38%. A 7-year age gap separated DKD and non-DKD patients (74 vs. 67 years, P < 0.0001). Additionally, individuals aged above 75 exhibited a substantial 22.58% increase in DKD risk (49.16% vs. 26.58%, P < 0.0001). Notably, linear regression analysis yielded a significant association between DKD and postoperative acute kidney injury (AKI), with DKD patients demonstrating 2.274-fold greater odds of AKI in contrast with non-DKD individuals (95% CI: 2.091-2.473). CONCLUSIONS: This study demonstrates that DKD is a significant risk factor for AKI in patients undergoing total hip arthroplasty. Optimizing preoperative kidney function through appropriate interventions might decrease the risk of poor prognosis in this population. More prospective research is warranted to investigate the potential of targeted kidney function improvement strategies in reducing AKI rates after THA. The findings of this study hold promise for enhancing preoperative counseling by surgeons, enabling them to provide DKD patients undergoing THA with more precise information regarding the risks associated with their condition.

Asymmetric total synthesis of polycyclic xanthenes and discovery of a WalK activator active against MRSA.

The development of new antibiotics continues to pose challenges, particularly considering the growing threat of multidrug-resistant Staphylococcus aureus. Structurally diverse natural products provide a promising source of antibiotics. Herein, we outline a concise approach for the collective asymmetric total synthesis of polycyclic xanthene myrtucommulone D and five related congeners. The strategy involves rapid assembly of the challenging benzopyrano[2,3-a]xanthene core, highly diastereoselective establishment of three contiguous stereocenters through a retro-hemiketalization/double Michael cascade reaction, and a Mitsunobu-mediated chiral resolution approach with high optical purity and broad substrate scope. Quantum mechanical calculations provide insight into stereoselective construction mechanism of the three contiguous stereocenters. Additionally, this work leads to the discovery of an antibacterial agent against both drug-sensitive and drug-resistant S. aureus. This compound operates through a unique mechanism that promotes bacterial autolysis by activating the two-component sensory histidine kinase WalK. Our research holds potential for future antibacterial drug development.

Advances in integrating single-cell sequencing data to unravel the mechanism of ferroptosis in cancer.

Ferroptosis, a commonly observed type of programmed cell death caused by abnormal metabolic and biochemical mechanisms, is frequently triggered by cellular stress. The occurrence of ferroptosis is predominantly linked to pathophysiological conditions due to the substantial impact of various metabolic pathways, including fatty acid metabolism and iron regulation, on cellular reactions to lipid peroxidation and ferroptosis. This mode of cell death serves as a fundamental factor in the development of numerous diseases, thereby presenting a range of therapeutic targets. Single-cell sequencing technology provides insights into the cellular and molecular characteristics of individual cells, as opposed to bulk sequencing, which provides data in a more generalized manner. Single-cell sequencing has found extensive application in the field of cancer research. This paper reviews the progress made in ferroptosis-associated cancer research using single-cell sequencing, including ferroptosis-associated pathways, immune checkpoints, biomarkers, and the identification of cell clusters associated with ferroptosis in tumors. In general, the utilization of single-cell sequencing technology has the potential to contribute significantly to the investigation of the mechanistic regulatory pathways linked to ferroptosis. Moreover, it can shed light on the intricate connection between ferroptosis and cancer. This technology holds great promise in advancing tumor-wide diagnosis, targeted therapy, and prognosis prediction.

Identification of LRRC46 as a novel candidate gene for high myopia.

High myopia (HM) is the primary cause of blindness, with the microstructural organization and composition of collagenous fibers in the cornea and sclera playing a crucial role in the biomechanical behavior of these tissues. In a previously reported myopic linkage region, MYP5 (17q21-22), a potential candidate gene, LRRC46 (c.C235T, p.Q79X), was identified in a large Han Chinese pedigree. LRRC46 is expressed in various eye tissues in humans and mice, including the retina, cornea, and sclera. In subsequent cell experiments, the mutation (c.C235T) decreased the expression of LRRC46 protein in human corneal epithelial cells (HCE-T). Further investigation revealed that Lrrc46-/- mice (KO) exhibited a classical myopia phenotype. The thickness of the cornea and sclera in KO mice became thinner and more pronounced with age, the activity of limbal stem cells decreased, and microstructural changes were observed in the fibroblasts of the sclera and cornea. We performed RNA-seq on scleral and corneal tissues of KO and normal control wild-type (WT) mice, which indicated a significant downregulation of the collagen synthesis-related pathway (extracellular matrix, ECM) in KO mice. Subsequent in vitro studies further indicated that LRRC46, a member of the important LRR protein family, primarily affected the formation of collagens. This study suggested that LRRC46 is a novel candidate gene for HM, influencing collagen protein VIII (Col8a1) formation in the eye and gradually altering the biomechanical structure of the cornea and sclera, thereby promoting the occurrence and development of HM.

Heterozygous variants in USP25 cause genetic generalized epilepsy.

USP25 encodes ubiquitin-specific proteases 25, a key member of deubiquitinating enzyme family and is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown etiology. Five heterozygous USP25 variants including two de novo and three co-segregated variants were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared to the East Asian population and all populations in the gnomAD database. The mean onset ages of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom except one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was ubiquitously expressed in mouse brain with two peaks on embryonic days (E14‒E16) and postnatal day 21, respectively. Similarly, USP25 expressed in fetus/early childhood stage with a second peak at approximately 12‒20 years old in human brain, consistent with the seizure onset age at infancy and juvenile in the patients. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knock-out mice, which showed increased seizure susceptibility compared to wild-type mice in pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we employed multiple functional detections. In HEK293T cells, the severe phenotype associated variant (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed a stable truncated dimers with increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del increased neuronal excitability in mice brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain.

Indeno[3,2-b]carbazole-Based Small Molecule Layer Enables Optimized Carrier Transport for PbS Quantum Dot NIR Photodetectors.

Colloidal quantum dots (CQDs) have garnered considerable attention for photodetectors (PDs), attributable to exceptional photoelectric properties and ease solution-based processing. However, the prevalent use of 1,2-ethanedithiol (EDT) as a hole transport layer (HTL) has limitations, such as energy level discrepancies, requisite oxidation, and intricate multilayer assembly. Organic p-type materials, lauded for their superior attributes and synthetic versatility, are now stepping forward as viable substitutes for conventional EDT HTLs. In this work, we introduced an organic HTL derived from indolo[3,2-b]carbazole, named ZL004, leading to a marked improvement in carrier generation and collection, facilitated by the optimized band alignment and enhanced interfacial charge dynamics. The ZL004-based PDs exhibit a photoresponsivity of 0.45 A/W, a noise current of 1.8 × 10-11 A Hz-0.5, a specific detectivity of 4.6 × 109 Jones, and an expansive linear dynamic range of 107 dB─surpassing EDT-based devices across the board, demonstrating the extraordinary property of organic p-type materials for CQD-based PDs.